1. Field of the Invention
The present invention relates generally to the fields of oncology, molecular biology, cell biology, and medicine. More particularly, it concerns prognosis or treatment of neoplasia or cancer using molecular markers.
2. Description of Related Art
Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC), and the cumulative risk of developing UC-associated CRC increases with the duration and extent of the disease (Eaden 2001; Zisman 2008). Therefore, UC patients who are at high-risk for CRC undergo periodic colonoscopic surveillance with multiple-step biopsies for the earlier diagnosis and treatment of UC-associated colorectal neoplasia (Hata 2003; Kornbluth 2004). However, it is unclear whether current surveillance colonoscopy is effective for early detection, as UC-associated CRC can be difficult to detect endoscopically, and to differentiate from inflammatory regenerative epithelium histologically (Fujii 2003). To improve surveillance efficacy, more effective markers for identifying patients at high risk for UC-associated CRC are needed.
Carcinogenesis in UC occurs in a histologically stepwise manner, sometimes called an “inflammation dysplasia carcinoma sequence” (Vogelstein 1988; Brentnall 1994). Carcinogenetic progression involves accumulation of genetic and epigenetic alterations (Itzkowitz 2004), that can occur in both non-neoplastic and neoplastic epithelium of patients with UC-associated neoplasia; this is referred to as a “field defect” (Hsieh 1998; Sato 2002; Watanabe, Int J Oncol; Watanabe, Clin Colorectal Cancer). These phenomena suggest that genetic and epigenetic changes in non-neoplastic epithelium could predict development of UC-associated neoplasia. In addition, the genetic features that lead to sporadic CRC—chromosome instability, microsatellite instability, and DNA hypermethylation—also occur in colitis-associated CRC. However, unlike normal colonic mucosa, cells of the inflammed colonic mucosa already have these pre-existing genetic alterations before appearance of s any histologic evidence of dysplasia or cancer. The reasons for these differences are not known, but oxidative stress is likely to be involved (Thomas A. Ullman 2011).
MicroRNAs (miRNAs) are small, non-coding RNAs involved in the regulation of gene expression by either repressing translation or directly cleaving target mRNAs (Iorio 2009). In addition, miRNAs affect pathogenesis of multiple cancer types, including CRC (Lu 2005; Calin 2006). They act as oncogenes or tumor suppressor genes, affecting early-stage carcinogenesis (Calin 2006). Ectopic miRNA expression has been seen in UC mucosa; miRNAs reportedly influence development and progression of UC and UC-associated neoplasia (Wu 2008; Kanaan 2012).
In several types of neoplasia, aberrant methylation of promoter-region CpG islands, as an epigenetic DNA modification, is associated with transcriptional inactivation of tumor suppressor genes; and can result in tumorigenesis. In colon tissues, CpG islands methylated in cancer have been divided into two groups: those that display cancer-restricted methylation (type C), and those that are methylated in (initially) normally aging epithelial cells (type A) (Toyota 1999). Age-related methylation has been proposed to identify and contribute to acquired predispositions to colorectal neoplasia because it parallels age-related increased cancer incidence, and can potentially alter the physiology of aging cells and tissues (Issa 1999).
However, there remains a need to develop a molecular test for neoplasia in UC patients, whose cancers may or may not develop in the same way as non-UC-neoplasia.